Agonists of the mu opioid receptor

ABSTRACT

The present technology is directed to compounds, compositions, and methods related to non-morphinan-like mu opioid receptor agonists. Compounds of the present technology demonstrate remarkable potency and selectivity for the mu opioid receptor, while also exhibiting a significant reduction (or, essentially, absence) of the negative side effects of many morphine-derived compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of and priority to U.S. ProvisionalAppl. No. 62/586,639, filed Nov. 15, 2017, the entirety of which ishereby incorporated by reference for any and all purposes.

U.S. GOVERNMENT RIGHTS

This invention was made with government support under DA018151 awardedby the National Institutes of Health. The government has certain rightsin the invention.

FIELD

The present technology is directed to compounds, compositions, andmethods related to non-morphinan-like mu opioid receptor (MOR) agonists.

SUMMARY

In an aspect, a compound according to Formula I is provided

or a pharmaceutically acceptable salt and/or solvate thereof, wherein

-   -   R¹ is

-   -   R² is a substituted C₁-C₃ alkyl, —C(O)H, —C(O)—C₁-C₃ alkyl, or        —C(O)—NR⁴R⁵, and        -   R³ is H, halo, substituted C₁-C₃ alkyl, or C₁-C₃ alkoxy; or    -   R² and R³ combined are heterocyclyl or heteroaryl; and    -   R⁴ and R⁵ are each independently H or C₁-C₃ alkyl.

In a related aspect, a composition is provided that includes thecompound and a pharmaceutically acceptable carrier.

In another related aspect, a pharmaceutical composition is provided, thepharmaceutical composition including an effective amount of the compoundfor treating pain.

DESCRIPTION OF THE DRAWINGS

FIGS. 1A-B show the results of the hot water tail-flick assay in micefor a compound of the present technology (compound 3.46) as compared tomorphine. For FIGS. 1A-B, data shown as mean±SEM.

FIGS. 2A-B compare the results of a hot water tail-flick assay in micethat received a single i.p. injection of (a) 10 mg/kg morphine, (b) 5mg/kg compound 3.46, (c) 5 mg/kg compound 3.46 followingpre-administration of beta-funaltrexamine (“β-FNA”; 5 mg/kg, s.c), and(d) vehicle. FIG. 2A provides the time course of analgesic effects inthe hot water tail-flick assay and FIG. 2B provides an area under thecurve (“AUC”) analysis, where **p<0.01, ***p<0.001, ****p<0.0001, drugcompared to vehicle, #p<0.05, ##p<0.01, ###p<0.001, ####p<0.0001compared to morphine, {circumflex over ( )}{circumflex over( )}{circumflex over ( )}{circumflex over ( )}p<0.0001 3.46 compared to3.46+β-FNA. Data shown as mean±SEM (N=5-7 per group).

DETAILED DESCRIPTION

In various aspects, the present technology provides compounds andmethods for agonizing a mu opioid receptor. The compounds providedherein can be formulated into pharmaceutical compositions andmedicaments that are useful in the disclosed methods. Also provided isthe use of the compounds in preparing pharmaceutical formulations andmedicaments.

The following terms are used throughout as defined below.

As used herein and in the appended claims, singular articles such as “a”and “an” and “the” and similar referents in the context of describingthe elements (especially in the context of the following claims) are tobe construed to cover both the singular and the plural, unless otherwiseindicated herein or clearly contradicted by context. Recitation ofranges of values herein are merely intended to serve as a shorthandmethod of referring individually to each separate value falling withinthe range, unless otherwise indicated herein, and each separate value isincorporated into the specification as if it were individually recitedherein. All methods described herein can be performed in any suitableorder unless otherwise indicated herein or otherwise clearlycontradicted by context. The use of any and all examples, or exemplarylanguage (e.g., “such as”) provided herein, is intended merely to betterilluminate the embodiments and does not pose a limitation on the scopeof the claims unless otherwise stated. No language in the specificationshould be construed as indicating any non-claimed element as essential.

As used herein, “about” will be understood by persons of ordinary skillin the art and will vary to some extent depending upon the context inwhich it is used. If there are uses of the term which are not clear topersons of ordinary skill in the art, given the context in which it isused, “about” will mean up to plus or minus 10% of the particularterm—for example, “about 10 wt. %” would mean “9 wt. % to 11 wt. %.”

Generally, reference to a certain element such as hydrogen or H is meantto include all isotopes of that element. For example, if an R group isdefined to include hydrogen or H, it also includes deuterium andtritium. Compounds comprising radioisotopes such as tritium, C¹⁴, P³²and S³⁵ are thus within the scope of the present technology. Proceduresfor inserting such labels into the compounds of the present technologywill be readily apparent to those skilled in the art based on thedisclosure herein.

In general, “substituted” refers to an organic group as defined below(e.g., an alkyl group) in which one or more bonds to a hydrogen atomcontained therein are replaced by a bond to non-hydrogen or non-carbonatoms. Substituted groups also include groups in which one or more bondsto a carbon(s) or hydrogen(s) atom are replaced by one or more bonds,including double or triple bonds, to a heteroatom. Thus, a substitutedgroup is substituted with one or more substituents, unless otherwisespecified. In some embodiments, a substituted group is substituted with1, 2, 3, 4, 5, or 6 substituents. Examples of substituent groupsinclude: halogens (i.e., F, Cl, Br, and I); hydroxyls; alkoxy, alkenoxy,aryloxy, aralkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy,and heterocyclylalkoxy groups; carbonyls (oxo); carboxylates; esters;urethanes; oximes; hydroxylamines; alkoxyamines; aralkoxyamines; thiols;sulfides; sulfoxides; sulfones; sulfonyls; pentafluorosulfanyl (i.e.,SF₅), sulfonamides; amines; N-oxides; hydrazines; hydrazides;hydrazones; azides; amides; ureas; amidines; guanidines; enamines;imides; isocyanates; isothiocyanates; cyanates; thiocyanates; imines;nitro groups; nitriles (i.e., CN); and the like.

Substituted ring groups such as substituted cycloalkyl, aryl,heterocyclyl and heteroaryl groups also include rings and ring systemsin which a bond to a hydrogen atom is replaced with a bond to a carbonatom. Therefore, substituted cycloalkyl, aryl, heterocyclyl andheteroaryl groups may also be substituted with substituted orunsubstituted alkyl, alkenyl, and alkynyl groups as defined below.

Alkyl groups include straight chain and branched chain alkyl groupshaving from 1 to 12 carbon atoms, and typically from 1 to 10 carbons or,in some embodiments, from 1 to 8, 1 to 6, or 1 to 4 carbon atoms. Alkylgroups may be substituted or unsubstituted. Examples of straight chainalkyl groups include groups such as methyl, ethyl, n-propyl, n-butyl,n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branchedalkyl groups include, but are not limited to, isopropyl, iso-butyl,sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropylgroups. Representative substituted alkyl groups may be substituted oneor more times with substituents such as those listed above, and includewithout limitation haloalkyl (e.g., trifluoromethyl), hydroxyalkyl,thioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl,carboxyalkyl, and the like.

Cycloalkyl groups include mono-, bi- or tricyclic alkyl groups havingfrom 3 to 12 carbon atoms in the ring(s), or, in some embodiments, 3 to10, 3 to 8, or 3 to 4, 5, or 6 carbon atoms. Cycloalkyl groups may besubstituted or unsubstituted. Exemplary monocyclic cycloalkyl groupsinclude, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, thecycloalkyl group has 3 to 8 ring members, whereas in other embodimentsthe number of ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7.Bi- and tricyclic ring systems include both bridged cycloalkyl groupsand fused rings, such as, but not limited to, bicyclo[2.1.1]hexane,adamantyl, decalinyl, and the like. Substituted cycloalkyl groups may besubstituted one or more times with, non-hydrogen and non-carbon groupsas defined above. However, substituted cycloalkyl groups also includerings that are substituted with straight or branched chain alkyl groupsas defined above. Representative substituted cycloalkyl groups may bemono-substituted or substituted more than once, such as, but not limitedto, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups, whichmay be substituted with substituents such as those listed above.

Cycloalkylalkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of an alkyl group is replaced with a bond to acycloalkyl group as defined above. Cycloalkylalkyl groups may besubstituted or unsubstituted. In some embodiments, cycloalkylalkylgroups have from 4 to 16 carbon atoms, 4 to 12 carbon atoms, andtypically 4 to 10 carbon atoms. Substituted cycloalkylalkyl groups maybe substituted at the alkyl, the cycloalkyl or both the alkyl andcycloalkyl portions of the group. Representative substitutedcycloalkylalkyl groups may be mono-substituted or substituted more thanonce, such as, but not limited to, mono-, di- or tri-substituted withsubstituents such as those listed above.

Alkenyl groups include straight and branched chain alkyl groups asdefined above, except that at least one double bond exists between twocarbon atoms. Alkenyl groups may be substituted or unsubstituted.Alkenyl groups have from 2 to 12 carbon atoms, and typically from 2 to10 carbons or, in some embodiments, from 2 to 8, 2 to 6, or 2 to 4carbon atoms. In some embodiments, the alkenyl group has one, two, orthree carbon-carbon double bonds. Examples include, but are not limitedto vinyl, allyl, —CH═CH(CH₃), —CH═C(CH₃)₂, —C(CH₃)═CH₂, —C(CH₃)═CH(CH₃),—C(CH₂CH₃)═CH₂, among others. Representative substituted alkenyl groupsmay be mono-substituted or substituted more than once, such as, but notlimited to, mono-, di- or tri-substituted with substituents such asthose listed above.

Cycloalkenyl groups include cycloalkyl groups as defined above, havingat least one double bond between two carbon atoms. Cycloalkenyl groupsmay be substituted or unsubstituted. In some embodiments thecycloalkenyl group may have one, two or three double bonds but does notinclude aromatic compounds. Cycloalkenyl groups have from 4 to 14 carbonatoms, or, in some embodiments, 5 to 14 carbon atoms, 5 to 10 carbonatoms, or even 5, 6, 7, or 8 carbon atoms. Examples of cycloalkenylgroups include cyclohexenyl, cyclopentenyl, cyclohexadienyl,cyclobutadienyl, and cyclopentadienyl.

Cycloalkenylalkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of the alkyl group is replaced with a bond to acycloalkenyl group as defined above. Cycloalkenylalkyl groups may besubstituted or unsubstituted. Substituted cycloalkenylalkyl groups maybe substituted at the alkyl, the cycloalkenyl or both the alkyl andcycloalkenyl portions of the group. Representative substitutedcycloalkenylalkyl groups may be substituted one or more times withsubstituents such as those listed above.

Alkynyl groups include straight and branched chain alkyl groups asdefined above, except that at least one triple bond exists between twocarbon atoms. Alkynyl groups may be substituted or unsubstituted.Alkynyl groups have from 2 to 12 carbon atoms, and typically from 2 to10 carbons or, in some embodiments, from 2 to 8, 2 to 6, or 2 to 4carbon atoms. In some embodiments, the alkynyl group has one, two, orthree carbon-carbon triple bonds. Examples include, but are not limitedto —C≡CH, —C≡CCH₃, —CH₂C≡CCH₃, —C≡CCH₂CH(CH₂CH₃)₂, among others.Representative substituted alkynyl groups may be mono-substituted orsubstituted more than once, such as, but not limited to, mono-, di- ortri-substituted with substituents such as those listed above.

Aryl groups are cyclic aromatic hydrocarbons that do not containheteroatoms. Aryl groups herein include monocyclic, bicyclic andtricyclic ring systems. Aryl groups may be substituted or unsubstituted.Thus, aryl groups include, but are not limited to, phenyl, azulenyl,heptalenyl, biphenyl, fluorenyl, phenanthrenyl, anthracenyl, indenyl,indanyl, pentalenyl, and naphthyl groups. In some embodiments, arylgroups contain 6-14 carbons, and in others from 6 to 12 or even 6-10carbon atoms in the ring portions of the groups. In some embodiments,the aryl groups are phenyl or naphthyl. The phrase “aryl groups”includes groups containing fused rings, such as fused aromatic-aliphaticring systems (e.g., indanyl, tetrahydronaphthyl, and the like).Representative substituted aryl groups may be mono-substituted (e.g.,tolyl) or substituted more than once. For example, monosubstituted arylgroups include, but are not limited to, 2-, 3-, 4-, 5-, or 6-substitutedphenyl or naphthyl groups, which may be substituted with substituentssuch as those listed above.

Aralkyl groups are alkyl groups as defined above in which a hydrogen orcarbon bond of an alkyl group is replaced with a bond to an aryl groupas defined above. Aralkyl groups may be substituted or unsubstituted. Insome embodiments, aralkyl groups contain 7 to 16 carbon atoms, 7 to 14carbon atoms, or 7 to 10 carbon atoms. Substituted aralkyl groups may besubstituted at the alkyl, the aryl or both the alkyl and aryl portionsof the group. Representative aralkyl groups include but are not limitedto benzyl and phenethyl groups and fused (cycloalkylaryl)alkyl groupssuch as 4-indanylethyl. Representative substituted aralkyl groups may besubstituted one or more times with substituents such as those listedabove.

Heterocyclyl groups include aromatic (also referred to as heteroaryl)and non-aromatic ring compounds containing 3 or more ring members, ofwhich one or more is a heteroatom such as, but not limited to, N, O, andS. Heterocyclyl groups may be substituted or unsubstituted. In someembodiments, the heterocyclyl group contains 1, 2, 3 or 4 heteroatoms.In some embodiments, heterocyclyl groups include mono-, bi- andtricyclic rings having 3 to 16 ring members, whereas other such groupshave 3 to 6, 3 to 10, 3 to 12, or 3 to 14 ring members. Heterocyclylgroups encompass aromatic, partially unsaturated and saturated ringsystems, such as, for example, imidazolyl, imidazolinyl andimidazolidinyl groups. The phrase “heterocyclyl group” includes fusedring species including those comprising fused aromatic and non-aromaticgroups, such as, for example, benzotriazolyl,2,3-dihydrobenzo[1,4]dioxinyl, and benzo[1,3]dioxolyl. The phrase alsoincludes bridged polycyclic ring systems containing a heteroatom suchas, but not limited to, quinuclidyl. The phrase includes heterocyclylgroups that have other groups, such as alkyl, oxo or halo groups, bondedto one of the ring members, referred to as “substituted heterocyclylgroups”. Heterocyclyl groups include, but are not limited to,aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl,thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl,furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl,pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl,piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl,tetrahydrothiopyranyl, oxathiane, dioxyl, dithianyl, pyranyl, pyridyl,pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl,dihydrodithiinyl, dihydrodithionyl, homopiperazinyl, quinuclidyl,indolyl, indolinyl, isoindolyl, azaindolyl (pyrrolopyridyl), indazolyl,indolizinyl, benzotriazolyl, benzimidazolyl, benzofuranyl,benzothiophenyl, benzthiazolyl, benzoxadiazolyl, benzoxazinyl,benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl,benzothiazolyl, benzothiadiazolyl, benzo[1,3]dioxolyl, pyrazolopyridyl,imidazopyridyl (azabenzimidazolyl), triazolopyridyl, isoxazolopyridyl,purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl,quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl,naphthyridinyl, pteridinyl, thianaphthyl, dihydrobenzothiazinyl,dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl,tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl,tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl,tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl,tetrahydrotriazolopyridyl, and tetrahydroquinolinyl groups.Representative substituted heterocyclyl groups may be mono-substitutedor substituted more than once, such as, but not limited to, pyridyl ormorpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, ordisubstituted with various substituents such as those listed above.

Heteroaryl groups are aromatic ring compounds containing 5 or more ringmembers, of which, one or more is a heteroatom such as, but not limitedto, N, O, and S. Heteroaryl groups may be substituted or unsubstituted.Heteroaryl groups include, but are not limited to, groups such aspyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl,benzothiophenyl, furanyl, benzofuranyl, indolyl, azaindolyl(pyrrolopyridinyl), indazolyl, benzimidazolyl, imidazopyridinyl(azabenzimidazolyl), pyrazolopyridinyl, triazolopyridinyl,benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,imidazopyridinyl, isoxazolopyridinyl, thianaphthyl, purinyl, xanthinyl,adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,quinoxalinyl, and quinazolinyl groups. Heteroaryl groups include fusedring compounds in which all rings are aromatic such as indolyl groupsand include fused ring compounds in which only one of the rings isaromatic, such as 2,3-dihydro indolyl groups. Representative substitutedheteroaryl groups may be substituted one or more times with varioussubstituents such as those listed above.

Heterocyclylalkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of an alkyl group is replaced with a bond to aheterocyclyl group as defined above. Heterocyclylalkyl groups may besubstituted or unsubstituted. Substituted heterocyclylalkyl groups maybe substituted at the alkyl, the heterocyclyl or both the alkyl andheterocyclyl portions of the group. Representative heterocyclyl alkylgroups include, but are not limited to, morpholin-4-yl-ethyl,furan-2-yl-methyl, imidazol-4-yl-methyl, pyridin-3-yl-methyl,tetrahydrofuran-2-yl-ethyl, and indol-2-yl-propyl. Representativesubstituted heterocyclylalkyl groups may be substituted one or moretimes with substituents such as those listed above.

Heteroaralkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of an alkyl group is replaced with a bond to aheteroaryl group as defined above. Heteroaralkyl groups may besubstituted or unsubstituted. Substituted heteroaralkyl groups may besubstituted at the alkyl, the heteroaryl or both the alkyl andheteroaryl portions of the group. Representative substitutedheteroaralkyl groups may be substituted one or more times withsubstituents such as those listed above.

Groups described herein having two or more points of attachment (i.e.,divalent, trivalent, or polyvalent) within the compound of the presenttechnology are designated by use of the suffix, “ene.” For example,divalent alkyl groups are alkylene groups, divalent aryl groups arearylene groups, divalent heteroaryl groups are divalent heteroarylenegroups, and so forth. Substituted groups having a single point ofattachment to the compound of the present technology are not referred tousing the “ene” designation. Thus, e.g., chloroethyl is not referred toherein as chloroethylene.

Alkoxy groups are hydroxyl groups (—OH) in which the bond to thehydrogen atom is replaced by a bond to a carbon atom of a substituted orunsubstituted alkyl group as defined above. Alkoxy groups may besubstituted or unsubstituted. Examples of linear alkoxy groups includebut are not limited to methoxy, ethoxy, propoxy, butoxy, pentoxy,hexoxy, and the like. Examples of branched alkoxy groups include but arenot limited to isopropoxy, sec-butoxy, tert-butoxy, isopentoxy,isohexoxy, and the like. Examples of cycloalkoxy groups include but arenot limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy, and the like. Representative substituted alkoxy groupsmay be substituted one or more times with substituents such as thoselisted above.

The terms “alkanoyl” and “alkanoyloxy” as used herein can refer,respectively, to —C(O)-alkyl groups and —O—C(O)-alkyl groups, eachcontaining 2-5 carbon atoms. Similarly, “aryloyl” and “aryloyloxy” referto —C(O)-aryl groups and —O—C(O)-aryl groups.

The terms “aryloxy” and “arylalkoxy” refer to, respectively, asubstituted or unsubstituted aryl group bonded to an oxygen atom and asubstituted or unsubstituted aralkyl group bonded to the oxygen atom atthe alkyl. Examples include but are not limited to phenoxy, naphthyloxy,and benzyloxy. Representative substituted aryloxy and arylalkoxy groupsmay be substituted one or more times with substituents such as thoselisted above.

The term “carboxylate” as used herein refers to a —COOH group.

The term “ester” as used herein refers to —COOR⁷⁰ and —C(O)O-G groups.R⁷⁰ is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl,alkynyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group asdefined herein. G is a carboxylate protecting group. Carboxylateprotecting groups are well known to one of ordinary skill in the art. Anextensive list of protecting groups for the carboxylate groupfunctionality may be found in Protective Groups in Organic Synthesis,Greene, T. W.; Wuts, P. G. M., John Wiley & Sons, New York, N.Y., (3rdEdition, 1999) which can be added or removed using the procedures setforth therein and which is hereby incorporated by reference in itsentirety and for any and all purposes as if fully set forth herein.

The term “amide” (or “amido”) includes C- and N-amide groups, i.e.,—C(O)NR⁷¹R⁷², and —NR⁷¹C(O)R⁷² groups, respectively. R⁷¹ and R⁷² areindependently hydrogen, or a substituted or unsubstituted alkyl,alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl orheterocyclyl group as defined herein. Amido groups therefore include butare not limited to carbamoyl groups (—C(O)NH₂) and formamide groups(—NHC(O)H). In some embodiments, the amide is —NR⁷¹C(O)—(C₁₋₅ alkyl) andthe group is termed “carbonylamino,” and in others the amide is—NHC(O)-alkyl and the group is termed “alkanoylamino.”

The term “nitrile” or “cyano” as used herein refers to the —CN group.

Urethane groups include N- and O-urethane groups, i.e., —NR⁷³C(O)OR⁷⁴and —OC(O)NR⁷³R⁷⁴ groups, respectively. R⁷³ and R⁷⁴ are independently asubstituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl,aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. R⁷³may also be H.

The term “amine” (or “amino”) as used herein refers to —NR⁷⁵R⁷⁶ groups,wherein R⁷⁵ and R⁷⁶ are independently hydrogen, or a substituted orunsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl,heterocyclylalkyl or heterocyclyl group as defined herein. In someembodiments, the amine is alkylamino, dialkylamino, arylamino, oralkylarylamino. In other embodiments, the amine is NH₂, methylamino,dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino,phenylamino, or benzylamino.

The term “sulfonamido” includes S- and N-sulfonamide groups, i.e.,—SO₂NR⁷⁸R⁷⁹ and —NR⁷⁸SO₂R⁷⁹ groups, respectively. R⁷⁸ and R⁷⁹ areindependently hydrogen, or a substituted or unsubstituted alkyl,alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, orheterocyclyl group as defined herein. Sulfonamido groups thereforeinclude but are not limited to sulfamoyl groups (—SO₂NH₂). In someembodiments herein, the sulfonamido is —NHSO₂-alkyl and is referred toas the “alkylsulfonylamino” group.

The term “thiol” refers to —SH groups, while “sulfides” include —SR⁸⁰groups, “sulfoxides” include —S(O)R⁸¹ groups, “sulfones” include —SO₂R⁸²groups, and “sulfonyls” include —SO₂OR⁸³. R⁸⁰, R⁸¹, R⁸², and R⁸³ areeach independently a substituted or unsubstituted alkyl, cycloalkyl,alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl groupas defined herein. In some embodiments the sulfide is an alkylthiogroup, —S-alkyl.

The term “urea” refers to —NR⁸⁴—C(O)—NR⁸⁵R⁸⁶ groups. R⁸⁴, R⁸⁵, and R⁸⁶groups are independently hydrogen, or a substituted or unsubstitutedalkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, orheterocyclylalkyl group as defined herein.

The term “amidine” refers to —C(NR⁸⁷)NR⁸⁸R⁸⁹ and —NR⁸⁷C(NR⁸⁸)R⁸⁹,wherein R⁸⁷, R⁸⁸, and R⁸⁹ are each independently hydrogen, or asubstituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylaralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

The term “guanidine” refers to —NR⁹⁰C(NR⁹¹)NR⁹²R⁹³, wherein R⁹⁰, R⁹¹,R⁹² and R⁹³ are each independently hydrogen, or a substituted orunsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl,heterocyclyl or heterocyclylalkyl group as defined herein.

The term “enamine” refers to —C(R⁹⁴)═C(R⁹⁵)NR⁹⁶R⁹⁷ and—NR⁹⁴C(R⁹⁵)═C(R⁹⁶)R⁹⁷, wherein R⁹⁴, R⁹⁵, R⁹⁶ and R⁹⁷ are eachindependently hydrogen, a substituted or unsubstituted alkyl,cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl orheterocyclylalkyl group as defined herein.

The term “halogen” or “halo” as used herein refers to bromine, chlorine,fluorine, or iodine. In some embodiments, the halogen is fluorine. Inother embodiments, the halogen is chlorine or bromine.

The term “hydroxyl” as used herein can refer to —OH or its ionized form,—O⁻. A “hydroxyalkyl” group is a hydroxyl-substituted alkyl group, suchas HO—CH₂—.

The term “imide” refers to —C(O)NR⁹⁸C(O)R⁹⁹, wherein R⁹⁸ and R⁹⁹ areeach independently hydrogen, or a substituted or unsubstituted alkyl,cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl orheterocyclylalkyl group as defined herein.

The term “imine” refers to —CR¹⁰⁰(NR¹⁰¹) and —N(CR¹⁰⁰R¹⁰¹) groups,wherein R¹⁰⁰ and R¹⁰¹ are each independently hydrogen or a substitutedor unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl,heterocyclyl or heterocyclylalkyl group as defined herein, with theproviso that R¹⁰⁰ and R¹⁰¹ are not both simultaneously hydrogen.

The term “nitro” as used herein refers to an —NO₂ group.

The term “trifluoromethyl” as used herein refers to —CF₃.

The term “trifluoromethoxy” as used herein refers to —OCF₃.

The term “azido” refers to —N₃.

The term “trialkyl ammonium” refers to a —N(alkyl)₃ group. Atrialkylammonium group is positively charged and thus typically has anassociated anion, such as halogen anion.

The term “isocyano” refers to —NC.

The term “isothiocyano” refers to —NCS.

The term “pentafluorosulfanyl” refers to —SF₅.

The phrase “selectively” or “selectivity” as used herein will beunderstood by persons of ordinary skill in the art and will vary to someextent depending upon the context in which the phrase is used. If thereare uses of the phrase which are not clear to persons of ordinary skillin the art, given the context in which the phrase is used, the phrase atminimum refers to the compounds acting through a specific mechanism ofaction, resulting in fewer off-target effects because the compoundstarget a particular receptor over other receptors, such as a mu (μ)opioid receptor (MOR) over a kappa (κ) opioid receptor (KOR) and/or adelta (δ) opioid receptor (DOR). The phrase may further be modified asdiscussed herein.

As will be understood by one skilled in the art, for any and allpurposes, particularly in terms of providing a written description, allranges disclosed herein also encompass any and all possible subrangesand combinations of subranges thereof. Any listed range can be easilyrecognized as sufficiently describing and enabling the same range beingbroken down into at least equal halves, thirds, quarters, fifths,tenths, etc. As a non-limiting example, each range discussed herein canbe readily broken down into a lower third, middle third and upper third,etc. As will also be understood by one skilled in the art all languagesuch as “up to,” “at least,” “greater than,” “less than,” and the likeinclude the number recited and refer to ranges which can be subsequentlybroken down into subranges as discussed above. Finally, as will beunderstood by one skilled in the art, a range includes each individualmember. Thus, for example, a group having 1-3 atoms refers to groupshaving 1, 2, or 3 atoms. Similarly, a group having 1-5 atoms refers togroups having 1, 2, 3, 4, or 5 atoms, and so forth.

Pharmaceutically acceptable salts of compounds described herein arewithin the scope of the present technology and include acid or baseaddition salts which retain the desired pharmacological activity and isnot biologically undesirable (e.g., the salt is not unduly toxic,allergenic, or irritating, and is bioavailable). When the compound ofthe present technology has a basic group, such as, for example, an aminogroup, pharmaceutically acceptable salts can be formed with inorganicacids (such as hydrochloric acid, hydroboric acid, nitric acid, sulfuricacid, and phosphoric acid), organic acids (e.g. alginate, formic acid,acetic acid, benzoic acid, gluconic acid, fumaric acid, oxalic acid,tartaric acid, lactic acid, maleic acid, citric acid, succinic acid,malic acid, methanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, and p-toluenesulfonic acid) or acidic amino acids (suchas aspartic acid and glutamic acid). When the compound of the presenttechnology has an acidic group, such as for example, a carboxylic acidgroup, it can form salts with metals, such as alkali and earth alkalimetals (e.g. Na⁺, Li⁺, K⁺, Ca²⁺, Mg²⁺, Zn²⁺), ammonia or organic amines(e.g. dicyclohexylamine, trimethylamine, triethylamine, pyridine,picoline, ethanolamine, diethanolamine, triethanolamine) or basic aminoacids (e.g. arginine, lysine and ornithine). Such salts can be preparedin situ during isolation and purification of the compounds or byseparately reacting the purified compound in its free base or free acidform with a suitable acid or base, respectively, and isolating the saltthus formed.

Those of skill in the art will appreciate that compounds of the presenttechnology may exhibit the phenomena of tautomerism, conformationalisomerism, geometric isomerism and/or stereoisomerism. As the formuladrawings within the specification and claims can represent only one ofthe possible tautomeric, conformational isomeric, stereochemical orgeometric isomeric forms, it should be understood that the presenttechnology encompasses any tautomeric, conformational isomeric,stereochemical and/or geometric isomeric forms of the compounds havingone or more of the utilities described herein, as well as mixtures ofthese various different forms.

“Tautomers” refers to isomeric forms of a compound that are inequilibrium with each other. The presence and concentrations of theisomeric forms will depend on the environment the compound is found inand may be different depending upon, for example, whether the compoundis a solid or is in an organic or aqueous solution. For example, inaqueous solution, quinazolinones may exhibit the following isomericforms, which are referred to as tautomers of each other:

As another example, guanidines may exhibit the following isomeric formsin protic organic solution, also referred to as tautomers of each other:

Because of the limits of representing compounds by structural formulas,it is to be understood that all chemical formulas of the compoundsdescribed herein represent all tautomeric forms of compounds and arewithin the scope of the present technology.

Stereoisomers of compounds (also known as optical isomers) include allchiral, diastereomeric, and racemic forms of a structure, unless thespecific stereochemistry is expressly indicated. Thus, compounds used inthe present technology include enriched or resolved optical isomers atany or all asymmetric atoms as are apparent from the depictions. Bothracemic and diastereomeric mixtures, as well as the individual opticalisomers can be isolated or synthesized so as to be substantially free oftheir enantiomeric or diastereomeric partners, and these stereoisomersare all within the scope of the present technology.

The compounds of the present technology may exist as solvates,especially hydrates. Hydrates may form during manufacture of thecompounds or compositions comprising the compounds, or hydrates may formover time due to the hygroscopic nature of the compounds. Compounds ofthe present technology may exist as organic solvates as well, includingDMF, ether, and alcohol solvates among others. The identification andpreparation of any particular solvate is within the skill of theordinary artisan of synthetic organic or medicinal chemistry.

The Present Technology

Pain affects nearly 115 million Americans, which is more than cancer,heart disease, and diabetes combined. Unfortunately, the use of opioids,one of the most common drug classes used to treat pain, is problematicdue to their high abuse liability. In 2014, an estimated 54 millionpeople over the age of 12 had used prescription drugs, such as opioids,non-medically in their lifetimes. According to the Centers for DiseaseControl and Prevention (CDC), 2014 had the highest rate of drug overdosedeaths than any year prior, with an estimated 40 Americans dying eachday from overdosing on prescription painkillers. Thus, a stronganalgesic devoid of abuse liabilities is desperately needed in anattempt to combat this trend and prevent these deaths.

The prototypical opioid, morphine, has been used for over a century forthe management of pain, and its powerful analgesic effects havestimulated innumerable synthetic and semi-synthetic investigations aimedat optimizing its biological effects. While these studies have resultedin most of the clinically useful treatments for pain such as codeine,oxycodone, meperidine, methadone, and fentanyl, these drugs are notwithout drawbacks. All of these morphine-derived compounds are mu opioidreceptor (MOR) agonists and suffer from adverse effects such assedation, tolerance, dependence, constipation, and respiratorydepression. Tolerance and dependence are particularly significanteffects because they can lead to opioid addiction, which is often themost concerning effect for both patients and prescribers.

Most clinically used opioids are structurally similar to morphine andthey all have very similar activity profiles. To date, it has been verydifficult to differentiate opioid-induced analgesic activity from abuseliability.

The present technology provides opioids that demonstrate remarkablepotency and selectivity for the MOR over the kappa opioid receptor (KOR)such as exhibiting EC₅₀ values for KOR>10,000 nM, while also exhibitinga significant reduction (or, essentially, absence) of the negative sideeffects of many morphine-derived compounds (such as tolerance, sedation,and/or liability for abuse).

Thus, in an aspect, a compound according to Formula I is provided

or a pharmaceutically acceptable salt and/or solvate thereof, wherein

-   -   R¹ is

-   -   R² is a substituted C₁-C₃ alkyl, —C(O)H, —C(O)—C₁-C₃ alkyl, or        —C(O)—NR⁴R⁵, and        -   R³ is H, halo, substituted C₁-C₃ alkyl, or C₁-C₃ alkoxy; or    -   R² and R³ combined are heterocyclyl or heteroaryl; and    -   R⁴ and R⁵ are each independently H or C₁-C₃ alkyl.

In any embodiment herein, R² may be a hydroxyl-substituted C₁-C₃ alkyl,a C₁-C₃ alkoxy substituted C₁-C₃ alkyl, —C(O)—C₁-C₃ alkyl, or—C(O)—NR⁴R⁵. For example, in any embodiment R² may be hydroxymethyl,(R)-1-hydroxyethyl, (S)-1-hydroxyethyl, methoxymethyl, or —C(O)—NH₂. Inany embodiment herein, it may be that R³ is H or R² and R³ combined areheterocyclyl or heteroaryl.

In any embodiment herein, it may be that when R² and R³ combined areheterocyclyl or heteroaryl, R¹ is

where X¹ and X² are each independently CH₂, O, or NH.

In any of the above embodiments, it may be that the compound is

or a pharmaceutically acceptable salt and/or solvate thereof of any oneof these.

In an aspect of the present technology, a composition is provided thatincludes any one of the herein-described embodiments of compounds ofFormula I and a pharmaceutically acceptable carrier. In a relatedaspect, a pharmaceutical composition is provided, the pharmaceuticalcomposition including an effective amount of the compound of any one ofthe aspects and embodiments of compounds of Formula I for treating painin a subject; and a pharmaceutically acceptable carrier. In a furtherrelated aspect, a method is provided that includes administering aneffective amount of a compound of any one of the embodiments ofcompounds of Formula I or administering a pharmaceutical compositionincluding an effective amount of a compound of any one of theembodiments of compounds of Formula I to a subject suffering from pain.

“Effective amount” refers to the amount of a compound or compositionrequired to produce a desired effect. One example of an effective amountincludes amounts or dosages that yield acceptable toxicity andbioavailability levels for therapeutic (pharmaceutical) use including,but not limited to, the treatment of pain. The effective amount of thecompound may selectively agonize the mu opioid receptor (MOR). Theeffective amount of the compound may selectively bind to the MOR atleast about 5 times more than the 6 opioid receptor (DOR); thus, theeffective amount of the compound may selectively bind to the MOR atleast about 10 times, at least about 25 times, at least about 50 times,or at least about 100 times more than the DOR. In any embodiment herein,including any of the above embodiments regarding the DOR, the effectiveamount of the compound may selectively bind to the MOR at least about 5times more than the kappa opioid receptor (KOR); thus, it may be thatthe effective amount of the compound selectively binds to the MOR atleast about 10 times more, at least 25 times more, at least about 50times more, or at least about 100 times more than the KOR. As usedherein, a “subject” or “patient” is a mammal, such as a cat, dog, rodentor primate. Typically the subject is a human, and, preferably, a humansuffering from or suspected of suffering from pain. The term “subject”and “patient” can be used interchangeably.

Thus, the instant present technology provides pharmaceuticalcompositions and medicaments comprising any of the compounds disclosedherein (e.g., compounds of Formula I) and a pharmaceutically acceptablecarrier or one or more excipients or fillers. The compositions may beused in the methods and treatments described herein. Such compositionsand medicaments include a therapeutically effective amount of anycompound as described herein, including but not limited to a compound offormula I. The pharmaceutical composition may be packaged in unit dosageform. The unit dosage form is effective in treating addiction byreducing desire for an addictive substance(s), and/or effective intreating a metabolic disorder by reducing symptoms associated with themetabolic disorder when administered to a subject in need thereof.

The pharmaceutical compositions and medicaments may be prepared bymixing one or more compounds of the present technology, pharmaceuticallyacceptable salts thereof, stereoisomers thereof, tautomers thereof, orsolvates thereof, with pharmaceutically acceptable carriers, excipients,binders, diluents or the like. The compounds and compositions describedherein may be used to prepare formulations and medicaments that preventor treat pain. Such compositions can be in the form of, for example,granules, powders, tablets, capsules, syrup, suppositories, injections,emulsions, elixirs, suspensions or solutions. The instant compositionscan be formulated for various routes of administration, for example, byoral, parenteral, topical, rectal, nasal, vaginal administration, or viaimplanted reservoir. Parenteral or systemic administration includes, butis not limited to, subcutaneous, intravenous, intraperitoneal, andintramuscular, injections. The following dosage forms are given by wayof example and should not be construed as limiting the instant presenttechnology.

For oral, buccal, and sublingual administration, powders, suspensions,granules, tablets, pills, capsules, gelcaps, and caplets are acceptableas solid dosage forms. These can be prepared, for example, by mixing oneor more compounds of the instant present technology, or pharmaceuticallyacceptable salts or tautomers thereof, with at least one additive suchas a starch or other additive. Suitable additives are sucrose, lactose,cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginates,chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins,collagens, casein, albumin, synthetic or semi-synthetic polymers orglycerides. Optionally, oral dosage forms can contain other ingredientsto aid in administration, such as an inactive diluent, or lubricantssuch as magnesium stearate, or preservatives such as paraben or sorbicacid, or antioxidants such as ascorbic acid, tocopherol or cysteine, adisintegrating agent, binders, thickeners, buffers, sweeteners,flavoring agents or perfuming agents. Tablets and pills may be furthertreated with suitable coating materials known in the art.

Liquid dosage forms for oral administration may be in the form ofpharmaceutically acceptable emulsions, syrups, elixirs, suspensions, andsolutions, which may contain an inactive diluent, such as water.Pharmaceutical formulations and medicaments may be prepared as liquidsuspensions or solutions using a sterile liquid, such as, but notlimited to, an oil, water, an alcohol, and combinations of these.Pharmaceutically suitable surfactants, suspending agents, emulsifyingagents, may be added for oral or parenteral administration.

As noted above, suspensions may include oils. Such oils include, but arenot limited to, peanut oil, sesame oil, cottonseed oil, corn oil andolive oil. Suspension preparation may also contain esters of fatty acidssuch as ethyl oleate, isopropyl myristate, fatty acid glycerides andacetylated fatty acid glycerides. Suspension formulations may includealcohols, such as, but not limited to, ethanol, isopropyl alcohol,hexadecyl alcohol, glycerol and propylene glycol. Ethers, such as butnot limited to, poly(ethyleneglycol), petroleum hydrocarbons such asmineral oil and petrolatum; and water may also be used in suspensionformulations.

Injectable dosage forms generally include aqueous suspensions or oilsuspensions which may be prepared using a suitable dispersant or wettingagent and a suspending agent. Injectable forms may be in solution phaseor in the form of a suspension, which is prepared with a solvent ordiluent. Acceptable solvents or vehicles include sterilized water,Ringer's solution, or an isotonic aqueous saline solution.Alternatively, sterile oils may be employed as solvents or suspendingagents. Typically, the oil or fatty acid is non-volatile, includingnatural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.

For injection, the pharmaceutical formulation and/or medicament may be apowder suitable for reconstitution with an appropriate solution asdescribed above. Examples of these include, but are not limited to,freeze dried, rotary dried or spray dried powders, amorphous powders,granules, precipitates, or particulates. For injection, the formulationsmay optionally contain stabilizers, pH modifiers, surfactants,bioavailability modifiers and combinations of these.

Compounds of the present technology may be administered to the lungs byinhalation through the nose or mouth. Suitable pharmaceuticalformulations for inhalation include solutions, sprays, dry powders, oraerosols containing any appropriate solvents and optionally othercompounds such as, but not limited to, stabilizers, antimicrobialagents, antioxidants, pH modifiers, surfactants, bioavailabilitymodifiers and combinations of these. The carriers and stabilizers varywith the requirements of the particular compound, but typically includenonionic surfactants (Tweens, Pluronics, or polyethylene glycol),innocuous proteins like serum albumin, sorbitan esters, oleic acid,lecithin, amino acids such as glycine, buffers, salts, sugars or sugaralcohols. Aqueous and nonaqueous (e.g., in a fluorocarbon propellant)aerosols are typically used for delivery of compounds of the presenttechnology by inhalation.

Dosage forms for the topical (including buccal and sublingual) ortransdermal administration of compounds of the present technologyinclude powders, sprays, ointments, pastes, creams, lotions, gels,solutions, and patches. The active component may be mixed under sterileconditions with a pharmaceutically-acceptable carrier or excipient, andwith any preservatives, or buffers, which may be required. Powders andsprays can be prepared, for example, with excipients such as lactose,talc, silicic acid, aluminum hydroxide, calcium silicates and polyamidepowder, or mixtures of these substances. The ointments, pastes, creamsand gels may also contain excipients such as animal and vegetable fats,oils, waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof. Absorption enhancers can also be used toincrease the flux of the compounds of the present technology across theskin. The rate of such flux can be controlled by either providing a ratecontrolling membrane (e.g., as part of a transdermal patch) ordispersing the compound in a polymer matrix or gel.

Besides those representative dosage forms described above,pharmaceutically acceptable excipients and carriers are generally knownto those skilled in the art and are thus included in the instant presenttechnology. Such excipients and carriers are described, for example, in“Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991),which is incorporated herein by reference.

The formulations of the present technology may be designed to beshort-acting, fast-releasing, long-acting, and sustained-releasing asdescribed below. Thus, the pharmaceutical formulations may also beformulated for controlled release or for slow release.

The instant compositions may also comprise, for example, micelles orliposomes, or some other encapsulated form, or may be administered in anextended release form to provide a prolonged storage and/or deliveryeffect. Therefore, the pharmaceutical formulations and medicaments maybe compressed into pellets or cylinders and implanted intramuscularly orsubcutaneously as depot injections or as implants such as stents. Suchimplants may employ known inert materials such as silicones andbiodegradable polymers.

Specific dosages may be adjusted depending on conditions of disease, theage, body weight, general health conditions, sex, and diet of thesubject, dose intervals, administration routes, excretion rate, andcombinations of drugs. Any of the above dosage forms containingeffective amounts are well within the bounds of routine experimentationand therefore, well within the scope of the instant present technology.

Those skilled in the art are readily able to determine an effectiveamount by simply administering a compound of the present technology to apatient in increasing amounts until, for example, the intensity of thepain decreases (e.g., as indicated by the patient). The compounds of thepresent technology can be administered to a patient at dosage levels inthe range of about 0.1 to about 1,000 mg per day. For a normal humanadult having a body weight of about 70 kg, a dosage in the range ofabout 0.01 to about 100 mg per kg of body weight per day is sufficient.The specific dosage used, however, can vary or may be adjusted asconsidered appropriate by those of ordinary skill in the art. Forexample, the dosage can depend on a number of factors including therequirements of the patient, the severity of the pain and thepharmacological activity of the compound being used. The determinationof optimum dosages for a particular patient is well known to thoseskilled in the art.

Various assays and model systems can be readily employed to determinethe therapeutic effectiveness of the treatment according to the presenttechnology. Effectiveness of the compositions and methods of the presenttechnology may also be demonstrated by a decrease in the symptoms ofpain, such as, for example, a decrease in movement and/or a decrease inresponse to external stimuli.

For each of the indicated conditions described herein, test subjectswill exhibit a 10%, 20%, 30%, 50% or greater reduction, up to a 75-90%,or 95% or greater, reduction, in one or more symptom(s) caused by, orassociated with, the disorder in the subject, compared toplacebo-treated or other suitable control subjects.

The compounds of the present technology can also be administered to apatient along with other conventional therapeutic agents that may beuseful in the treatment of pain. The administration may include oraladministration, parenteral administration, or nasal administration. Inany of these embodiments, the administration may include subcutaneousinjections, intravenous injections, intraperitoneal injections, orintramuscular injections. In any of these embodiments, theadministration may include oral administration. The methods of thepresent technology can also comprise administering, either sequentiallyor in combination with one or more compounds of the present technology,a conventional therapeutic agent in an amount that can potentially orsynergistically be effective for the treatment of pain.

In one aspect, a compound of the present technology is administered to apatient in an amount or dosage suitable for therapeutic use. Generally,a unit dosage comprising a compound of the present technology will varydepending on patient considerations. Such considerations include, forexample, age, protocol, condition, sex, extent of disease,contraindications, concomitant therapies and the like. An exemplary unitdosage based on these considerations can also be adjusted or modified bya physician skilled in the art. For example, a unit dosage for a patientcomprising a compound of the present technology can vary from 1×10⁻⁴g/kg to 1 g/kg, preferably, 1×10⁻³ g/kg to 1.0 g/kg. Dosage of acompound of the present technology can also vary from 0.01 mg/kg to 100mg/kg or, preferably, from 0.1 mg/kg to 10 mg/kg.

A compound of the present technology can also be modified, for example,by the covalent attachment of an organic moiety or conjugate to improvepharmacokinetic properties, toxicity or bioavailability (e.g., increasedin vivo half-life). The conjugate can be a linear or branchedhydrophilic polymeric group, fatty acid group or fatty acid ester group.A polymeric group can comprise a molecular weight that can be adjustedby one of ordinary skill in the art to improve, for example,pharmacokinetic properties, toxicity or bioavailability. Exemplaryconjugates can include a polyalkane glycol (e.g., polyethylene glycol(PEG), polypropylene glycol (PPG)), carbohydrate polymer, amino acidpolymer or polyvinyl pyrolidone and a fatty acid or fatty acid estergroup, each of which can independently comprise from about eight toabout seventy carbon atoms. Conjugates for use with a compound of thepresent technology can also serve as linkers to, for example, anysuitable substituents or groups, radiolabels (marker or tags), halogens,proteins, enzymes, polypeptides, other therapeutic agents (for example,a pharmaceutical or drug), nucleosides, dyes, oligonucleotides, lipids,phospholipids and/or liposomes. In one aspect, conjugates can includepolyethylene amine (PEI), polyglycine, hybrids of PEI and polyglycine,polyethylene glycol (PEG) or methoxypolyethylene glycol (mPEG). Aconjugate can also link a compound of the present technology to, forexample, a label (fluorescent or luminescent) or marker (radionuclide,radioisotope and/or isotope) to comprise a probe of the presenttechnology. Conjugates for use with a compound of the present technologycan, in one aspect, improve in vivo half-life. Other exemplaryconjugates for use with a compound of the present technology as well asapplications thereof and related techniques include those generallydescribed by U.S. Pat. No. 5,672,662, which is hereby incorporated byreference herein.

In another aspect, the present technology provides methods ofidentifying a target of interest including contacting the target ofinterest with a detectable or imaging effective quantity of a labeledcompound of the present technology. A detectable or imaging effectivequantity is a quantity of a labeled compound of the present technologynecessary to be detected by the detection method chosen. For example, adetectable quantity can be an administered amount sufficient to enabledetection of binding of the labeled compound to a target of interestincluding, but not limited to, a MOR. Suitable labels are known by thoseskilled in the art and can include, for example, radioisotopes,radionuclides, isotopes, fluorescent groups, biotin (in conjunction withstreptavidin complexation), and chemiluminescent groups. Upon binding ofthe labeled compound to the target of interest, the target may beisolated, purified and further characterized such as by determining theamino acid sequence.

The terms “associated” and/or “binding” can mean a chemical or physicalinteraction, for example, between a compound of the present technologyand a target of interest. Examples of associations or interactionsinclude covalent bonds, ionic bonds, hydrophilic-hydrophilicinteractions, hydrophobic-hydrophobic interactions and complexes.Associated can also refer generally to “binding” or “affinity” as eachcan be used to describe various chemical or physical interactions.Measuring binding or affinity is also routine to those skilled in theart. For example, compounds of the present technology can bind to orinteract with a target of interest or precursors, portions, fragmentsand peptides thereof and/or their deposits.

The examples herein are provided to illustrate advantages of the presenttechnology and to further assist a person of ordinary skill in the artwith preparing or using the compounds of the present technology orsalts, pharmaceutical compositions, derivatives, solvates, metabolites,prodrugs, racemic mixtures or tautomeric forms thereof. The examplesherein are also presented in order to more fully illustrate thepreferred aspects of the present technology. The examples should in noway be construed as limiting the scope of the present technology, asdefined by the appended claims. The examples can include or incorporateany of the variations, aspects or aspects of the present technologydescribed above. The variations, aspects or aspects described above mayalso further each include or incorporate the variations of any or allother variations, aspects or aspects of the present technology.

Examples

General Synthetic and Analytical Details:

Salvinorin A was isolated from the leaves of Salvia divinorum andconverted to salvinorin B as previously described in Harding, W. W.,Schmidt, M., Tidgewell, K., Kalman, P., Holden, K. G., Gilmour, B.,Navarro, H., Rothman, R. B., and Prisinzano, T. E. (2006) Syntheticstudies of neoclerodane diterpenes from Salvia divinorum: semisynthesisof salvinicins A and B and other chemical transformations of salvinorinA, J. Nat. Prod. 69, 107-112, incorporated herein by reference. Allother chemical reagents were purchased from commercial suppliers andused without further purification. All solvents were obtained from asolvent purification system in which solvent was passed through twocolumns of activated alumina under argon. Reactions performed instandard glassware were performed under an atmosphere of argon usingglassware dried overnight in an oven at 120° C. and cooled under astream of argon. Reactions were monitored by thin-layer chromatography(TLC) on 0.25 mm Analtech GHLF silica gel plates and visualized using aUV Lamp (254 nm) and vanillin solution. Flash column chromatography wasperformed on silica gel (4-63 mm) from Sorbent Technologies. ¹H and ¹³CNMR were recorded a 500 MHz Bruker AVIII spectrometer equipped with acryogenically-cooled carbon observe probe or a 400 MHz Bruker AVIIIHDspectrometer using tetramethyl silane as an internal standard. Chemicalshifts (δ) are reported in ppm and coupling constants (J) are reportedin Hz. High-resolution mass spectrum (HRMS) was performed on a LCTPremier (Micromass Ltd., Manchester UK) time of flight mass spectrometerwith an electrospray ion source in either positive or negative mode.Melting points were measured with a Thomas Capillary Melting PointApparatus and are uncorrected. HPLC was carried out on an Agilent 1100series HPLC system with diode array detection at 209 nm on an AgilentEclipse XDB-C18 column (250×10 mm, 5 mm). Compounds were identified as≥95% pure by HPLC before all in vitro and in vivo analyses.

Representative Synthetic Procedures for Representative Compounds ofStudy

Oxidation of Salvinorin B

(2S,4aR,6aR,7R,10aR,10bR)-methyl2-(furan-3-yl)-9-hydroxy-6a,10b-dimethyl-4,10-dioxo-2,4,4a,5,6,6a,7,10,10a,10b-decahydro-1H-benzo[f]isochromene-7-carboxylate(2)

A combination of CH₂Cl₂ (40 mL) and MeOH (40 mL) was added to a flaskcontaining Salvinorin B (1, see Scheme 1 below) (250 mg, 0.640 mmol) andCu(OAc)₂ (349 mg, 1.92 mmol). After stirring overnight at RT thereaction was concentrated in vacuo. The residue was redissolved inCH₂Cl₂ (40 mL) and H₂O (40 mL). The aqueous layer was reextracted withCH₂Cl₂ (2×40 mL). The combined organic layers were washed with saturatedNH₄Cl (50 mL) and brine (50 mL) then dried over Na₂SO₄. The solvent wasremoved in vacuo and the residue purified via FCC eluting with 12.5%EtOAc/CH₂Cl₂ to yield 1 (43 mg, 17%) and an inseparable mixture oftautomers, herein represented by the indicated structure 2 (139 mg,52%). ¹H NMR (500 MHz, CDCl₃) δ 7.44 (m, 1H), 7.42 (m, 1H), 6.41 (dd,J=0.80, 1.79 Hz, 1H), 6.02 (d, J=2.50 Hz, 1H), 5.59 (dd, J=5.25, 11.62Hz, 1H), 3.76 (s, 3H), 3.41 (d, J=2.49 Hz, 1H), 3.14 (dd, J=5.13, 13.35Hz, 1H), 2.33 (s, 1H), 2.18 (m, 2H), 2.01 (m, 1H), 1.67 (m, 3H), 1.36(s, 3H), 1.11 (s, 3H). 13C NMR (126 MHz, CDCl₃) δ 194.70, 171.32,171.25, 146.69, 143.77, 139.38, 125.46, 112.18, 108.42, 71.92, 62.70,55.98, 52.24, 51.27, 44.67, 43.88, 38.20, 35.78, 17.86, 16.64, 14.72.HRMS calculated for C₂₁₁-12407: [M+Na]⁺: 411.1409 (found); 411.1420(calc). Melting point: 165-170° C. (dec).

General Acylation Procedure.

An oven-dried flask was charged with 2 (40 mg, 0.103 mmol), EDC.HCl(29.5 mg, 0.154 mmol), DMAP (18.8 mg, 0.154 mmol), and the appropriateacid (0.154 mmol). To the flask was added CH₂Cl₂ (8 mL). After stirringovernight at RT the reaction was quenched with HCl (1 M, 8 mL) and theorganic layer rinsed sequentially with saturated NaHCO₃ (8 mL) and brine(8 mL) then dried over Na₂SO₄. The solvent was removed in vacuo and theresulting residue purified by flash column chromatography (“FCC”)eluting with 30-35% EtOAc/Pent. Compounds <95% pure as indicated by HPLCwere further purified by reverse phase semi-preparatory HPLC.

Representative Compounds of Studies

Methyl(2S,4aR,6aR,7R,10aR,10bR)-9-((benzofuran-6-carbonyl)oxy)-2-(furan-3-yl)-6a,10b-dimethyl-4,10-dioxo-1,4,4a,5,6,6a,7,10,10a,10b-decahydro-2H-benzo[f]isochromene-7-carboxylate(3.44)

¹H NMR (500 MHz, CDCl₃) 8.28 (p, J=0.8 Hz, 1H), 8.01 (dd, J=8.2, 1.5 Hz,1H), 7.80 (d, J=2.2 Hz, 1H), 7.68 (dd, J=8.2, 0.6 Hz, 1H), 7.49-7.36 (m,2H), 6.85 (dd, J=2.2, 1.0 Hz, 1H), 6.68 (d, J=2.2 Hz, 1H), 6.39 (dd,J=1.9, 0.9 Hz, 1H), 5.60-5.46 (m, 1H), 3.81 (s, 3H), 3.61 (d, J=2.2 Hz,1H), 3.08 (dd, J=13.7, 5.3 Hz, 1H), 2.49 (s, 1H), 2.26-2.17 (m, 1H),2.13 (dt, J=13.2, 2.7 Hz, 1H), 1.79-1.58 (m, 2H), 1.39 (s, 3H), 1.26 (d,J=2.2 Hz, 5H). ¹³C NMR (126 MHz, CDCl₃) δ 190.96, 171.39, 170.40,164.78, 154.30, 148.44, 145.52, 143.65, 139.36, 132.69, 129.94, 125.42,124.74, 124.25, 121.15, 113.87, 108.45, 106.92, 72.07, 63.46, 56.51,52.47, 51.38, 44.20, 43.80, 38.46, 35.85, 17.96, 16.84, 14.86. HRMScalculated for C₃₀H₂₈O₉ [M+H]⁺: 533.1819 (found); 533.1806 (calcd).Melting point: 156-157° C. (decomp).

Methyl(2S,4aR,6aR,7R,10aR,10bR)-9-((benzofuran-5-carbonyl)oxy)-2-(furan-3-yl)-6a,10b-dimethyl-4,10-dioxo-1,4,4a,5,6,6a,7,10,10a,10b-decahydro-2H-benzo[f]isochromene-7-carboxylate(3.45)

¹H NMR (500 MHz, CDCl₃) 8.46-8.40 (m, 1H), 8.08 (dd, J=8.7, 1.8 Hz, 1H),7.71 (d, J=2.2 Hz, 1H), 7.57 (dt, J=8.7, 0.8 Hz, 1H), 7.48-7.34 (m, 2H),6.86 (dd, J=2.2, 1.0 Hz, 1H), 6.68 (d, J=2.2 Hz, 1H), 6.39 (dd, J=2.0,0.9 Hz, 1H), 5.62-5.47 (m, 1H), 3.80 (s, 3H), 3.61 (d, J=2.2 Hz, 1H),3.08 (dd, J=13.7, 5.3 Hz, 1H), 2.49 (s, 1H), 2.20 (ddt, J=12.6, 6.9, 3.5Hz, 2H), 2.12 (dt, J=13.1, 2.7 Hz, 1H), 1.79-1.63 (m, 3H), 1.39 (s, 3H),1.25 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 191.04, 171.39, 170.42, 164.76,157.96, 146.54, 145.52, 143.65, 139.36, 129.92, 127.66, 126.67, 125.41,124.67, 123.18, 111.63, 108.45, 107.13, 72.06, 63.45, 56.51, 52.47,51.38, 44.20, 43.80, 38.47, 35.85, 17.96, 16.84, 14.86. HRMS calculatedfor C₃₀H₂₈O₉ [M+H]⁺: 533.1797 (found); 533.1806 (calcd). Melting point:112-115° C.

Methyl(2S,4aR,6aR,7R,10aR,10bR)-2-(furan-3-yl)-9-((4-(hydroxymethyl)benzoyl)oxy)-6a,10b-dimethyl-4,10-dioxo-1,4,4a,5,6,6a,7,10,10a,10b-decahydro-2H-benzo[f]isochromene-7-carboxylate(3.46)

4-(TBSOCH₂)benzoic acid was used in the acylation of 2 to provide aTBS-protected coupling product. To a flask containing the crudeTBS-protected coupling product (0.2 mmol) was added a 1:1 mixture ofMeOH and acetone (6 mL total) followed by a solution of KHSO₄ (0.1 mmol,0.5 eq.) in 3 mL of H₂O. Reaction is a white suspension after wateraddition and was stirred overnight at r.t. Upon reaction completion, asmonitored by TLC, the solvent was evaporated and the product wasextracted from water (10 mL) into EtOAc (3×10 mL). The combined organiclayers were washed with brine, dried over Na₂SO₄, and solvent wasremoved. The compound was purified by FCC (50% EtOAc/Pentane). ¹H NMR(500 MHz, CDCl₃) 8.14-8.02 (m, 2H), 7.48 (d, J=8.3 Hz, 2H), 7.45-7.36(m, 2H), 6.66 (d, J=2.2 Hz, 1H), 6.39 (dd, J=1.9, 0.9 Hz, 1H), 5.54 (dd,J=11.5, 5.3 Hz, 1H), 4.80 (d, J=2.6 Hz, 2H), 3.80 (s, 3H), 3.60 (d,J=2.3 Hz, 1H), 3.06 (dd, J=13.7, 5.3 Hz, 1H), 2.47 (s, 1H), 2.24-2.16(m, 2H), 2.12 (dt, J=13.4, 2.7 Hz, 1H), 1.90 (s, 1H), 1.77-1.64 (m, 3H),1.37 (s, 3H), 1.24 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 190.90, 171.40,170.39, 164.40, 147.14, 145.42, 143.66, 139.37, 130.53, 129.99, 127.37,126.55, 125.40, 108.44, 72.06, 64.57, 63.44, 56.49, 52.48, 51.36, 44.19,43.79, 38.45, 35.84, 17.94, 16.82, 14.85. HRMS calculated for C₂₉H₃₀O₉[M+H]⁺: 523.1964 (found); 523.1963 (calcd). Melting point: 115-118° C.

Methyl(2S,4aR,6aR,7R,10aR,10bR)-2-(furan-3-yl)-9-((3-(hydroxymethyl)benzoyl)oxy)-6a,10b-dimethyl-4,10-dioxo-1,4,4a,5,6,6a,7,10,10a,10b-decahydro-2H-benzo[f]isochromene-7-carboxylate(3.47)

3-(TBSOCH₂)benzoic acid was used in the acylation of 2 to provide aTBS-protected coupling product. To a flask containing the crudeTBS-protected coupling product (0.2 mmol) was added a 1:1 mixture ofMeOH and acetone (6 mL total) followed by a solution of KHSO₄ (0.1 mmol,0.5 eq.) in 3 mL of H₂O. Reaction is a white suspension after wateraddition and was stirred overnight at r.t. Upon reaction completion, asmonitored by TLC, the solvent was evaporated and the product wasextracted from water (10 mL) into EtOAc (3×10 mL). The combined organiclayers were washed with brine, dried over Na₂SO₄, and solvent wasremoved. The compound was purified by FCC (50% EtOAc/Pentane). ¹H NMR(500 MHz, CDCl₃) 8.11 (d, J=1.7 Hz, 1H), 8.03 (d, J=7.8 Hz, 1H), 7.64(d, J=7.6 Hz, 1H), 7.48 (t, J=7.7 Hz, 1H), 7.43-7.37 (m, 2H), 6.66 (d,J=2.1 Hz, 1H), 6.39 (d, J=1.8 Hz, 1H), 5.54 (dd, J=11.5, 5.3 Hz, 1H),4.77 (s, 2H), 3.80 (s, 3H), 3.60 (d, J=2.1 Hz, 1H), 3.06 (dd, J=13.7,5.4 Hz, 1H), 2.47 (s, 1H), 2.24-2.07 (m, 3H), 1.85 (s, 1H), 1.77-1.63(m, 3H), 1.37 (s, 3H), zj1.24 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ190.87, 171.38, 170.37, 164.47, 145.45, 143.67, 141.56, 139.38, 132.31,129.98, 129.49, 128.90, 128.56, 128.52, 125.44, 108.45, 72.06, 64.63,63.49, 56.51, 52.46, 51.38, 44.22, 43.82, 38.48, 35.86, 17.97, 16.82,14.86. HRMS calculated for C₂₉H₃₀O₉ [M+H]⁺: 523.1959 (found); 523.1963(calcd). Melting point: 104-106° C.

Methyl(2S,4aR,6aR,7R,10aR,10bR)-2-(furan-3-yl)-9-((4-(methoxymethyl)benzoyl)oxy)-6a,10b-dimethyl-4,10-dioxo-1,4,4a,5,6,6a,7,10,10a,10b-decahydro-2H-benzo[f]isochromene-7-carboxylate(3.48)

¹H NMR (500 MHz, CDCl₃) 8.17-8.00 (m, 2H), 7.47-7.43 (m, 2H), 7.41 (dd,J=1.6, 0.9 Hz, 1H), 7.39 (t, J=1.7 Hz, 1H), 6.66 (d, J=2.1 Hz, 1H), 6.39(dd, J=1.9, 0.9 Hz, 1H), 5.60-5.48 (m, 1H), 4.54 (s, 2H), 3.80 (s, 3H),3.60 (d, J=2.3 Hz, 1H), 3.42 (s, 3H), 3.07 (dd, J=13.7, 5.3 Hz, 1H),2.47 (s, 1H), 2.20 (ddd, J=12.2, 6.4, 3.1 Hz, 2H), 2.12 (dt, J=13.1, 2.7Hz, 1H), 1.80-1.62 (m, 3H), 1.38 (s, 3H), 1.24 (s, 3H). ¹³C NMR (126MHz, CDCl₃) δ 190.90, 171.38, 170.38, 164.42, 145.43, 144.74, 143.66,139.36, 130.42, 129.97, 127.42, 127.28, 125.41, 108.44, 73.90, 72.05,63.45, 58.45, 56.49, 52.47, 51.37, 44.19, 43.80, 38.45, 35.84, 17.95,16.82, 14.85. HRMS calculated for C₃₀H₃₂O₉ [M+Na]⁺: 559.1922 (found);559.1944 (calcd). Melting point: 135-140° C.

Methyl(2S,4aR,6aR,7R,10aR,10bR)-9-((4-carbamoylbenzyl)oxy)-2-(furan-3-yl)-6a,10b-dimethyl-4,10-dioxo-1,4,4a,5,6,6a,7,10,10a,10b-decahydro-2H-benzo[f]isochromene-7-carboxylate(3.49)

¹H NMR (500 MHz, CDCl₃) 8.26-8.09 (m, 2H), 7.96-7.84 (m, 2H), 7.47-7.30(m, 2H), 6.70 (d, J=2.2 Hz, 1H), 6.39 (dd, J=1.9, 0.9 Hz, 1H), 6.11 (d,J=21.1 Hz, 1H), 5.67 (s, 1H), 5.55 (dd, J=11.6, 5.5 Hz, 1H), 3.81 (s,3H), 3.80 (s, 1H), 3.61 (d, J=2.2 Hz, 1H), 3.06 (dd, J=13.7, 5.3 Hz,1H), 2.48 (s, 1H), 2.26-2.14 (m, 2H), 2.16-2.09 (m, 1H), 1.46 (s, 1H),1.38 (s, 3H), 1.35 (s, 1H), 1.25 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ190.73, 171.45, 170.31, 167.89, 163.67, 145.28, 143.70, 139.37, 137.95,131.36, 130.58, 130.26, 127.60, 125.38, 108.43, 72.02, 63.48, 56.47,52.53, 51.36, 44.25, 43.81, 38.45, 35.86, 17.94, 16.83, 14.86. HRMScalculated for C₂₉H₃₀NO₉ [M+Na]⁺: 558.1728 (found); 558.1740 (calcd).Melting point: 201-203° C.

Methyl(2S,4aR,6aR,7R,10aR,10bR)-9-((3-carbamoylbenzyl)oxy)-2-(furan-3-yl)-6a,10b-dimethyl-4,10-dioxo-1,4,4a,5,6,6a,7,10,10a,10b-decahydro-2H-benzo[f]isochromene-7-carboxylate(3.50)

¹H NMR (500 MHz, CDCl₃) 8.51 (dt, J=4.1, 1.7 Hz, 1H), 8.25 (ddt, J=7.8,3.2, 1.4 Hz, 1H), 8.14 (dq, J=7.8, 1.4 Hz, 1H), 7.59 (td, J=7.8, 1.5 Hz,1H), 7.44-7.36 (m, 2H), 6.68 (d, J=2.2 Hz, 1H), 6.54-6.40 (m, 1H), 6.38(dt, J=1.8, 0.9 Hz, 1H), 6.19-5.99 (m, 1H), 5.53 (ddd, J=13.2, 8.3, 5.4Hz, 1H), 3.80 (d, J=4.1 Hz, 3H), 3.62 (d, J=2.2 Hz, 1H), 3.04 (td,J=13.5, 12.9, 5.3 Hz, 1H), 2.50 (s, 1H), 2.20 (ddd, J=16.0, 9.1, 3.2 Hz,2H), 2.12 (dd, J=13.3, 3.6 Hz, 1H), 1.81-1.62 (m, 2H), 1.44 (s, 1H),1.36 (s, 3H), 1.23 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 190.82, 171.43,170.35, 168.05, 163.77, 145.24, 143.68, 139.40, 133.96, 133.46, 133.07,130.31, 129.21, 128.84, 128.70, 125.35, 108.44, 72.02, 63.34, 56.40,52.52, 51.26, 44.24, 43.71, 38.40, 35.82, 17.93, 16.82, 14.84. HRMScalculated for C₂₉H₃₀NO₉ [M+Na]⁺: 558.1754 (found); 558.1740 (calcd).Melting point: 199-201° C.

(2S,4aR,6aR,7R,10aR,10bR)-2-(furan-3-yl)-7-(methoxycarbonyl)-6a,10b-dimethyl-4,10-dioxo-1,4,4a,5,6,6a,7,10,10a,10b-decahydro-2H-benzo[f]isochromen-9-yl3-oxoisoindoline-5-carboxylate (3.51)

¹H NMR (500 MHz, CDCl₃) 8.69-8.56 (m, 1H), 8.31 (ddd, J=7.9, 2.8, 1.6Hz, 1H), 7.61 (dd, J=7.9, 0.9 Hz, 1H), 7.55 (s, 1H), 7.42 (ddt, J=2.6,1.8, 0.8 Hz, 1H), 7.39 (t, J=1.7 Hz, 1H), 6.70 (d, J=2.2 Hz, 1H), 6.39(dd, J=1.9, 0.9 Hz, 1H), 5.58-5.51 (m, 1H), 4.56 (d, J=2.7 Hz, 2H), 3.81(s, 2H), 3.62 (d, J=2.2 Hz, 1H), 3.06 (dd, J=13.8, 5.5 Hz, 1H), 2.49 (s,1H), 2.25-2.17 (m, 2H), 2.16-2.08 (m, 1H), 2.01 (s, 1H), 1.84-1.61 (m,3H), 1.38 (s, 3H), 1.25 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 190.72,171.39, 170.54, 170.30, 163.77, 148.90, 145.30, 143.67, 139.36, 133.48,132.80, 130.23, 128.75, 126.06, 125.40, 123.69, 108.44, 72.04, 63.41,56.43, 52.50, 51.32, 45.89, 44.22, 43.75, 38.40, 35.85, 17.94, 16.81,14.84. HRMS calculated for C₃₀H₂₉O₉N [M+H]⁺: 548.1910 (found); 548.19151(calcd). Melting point: 189-194° C.

(2S,4aR,6aR,7R,10aR,10bR)-2-(furan-3-yl)-7-(methoxycarbonyl)-6a,10b-dimethyl-4,10-dioxo-1,4,4a,5,6,6a,7,10,10a,10b-decahydro-2H-benzo[f]isochromen-9-yl1-oxoisoindoline-5-carboxylate (3.52)

¹H NMR (500 MHz, CDCl₃) 8.26-8.19 (m, 2H), 7.97 (d, J=8.3 Hz, 1H), 7.60(s, 1H), 7.45-7.25 (m, 3H), 6.71 (d, J=2.1 Hz, 1H), 6.39 (dd, J=2.0, 0.9Hz, 1H), 5.54 (dd, J=11.5, 5.4 Hz, 1H), 4.54 (s, 2H), 3.81 (s, 3H), 3.62(d, J=2.2 Hz, 1H), 3.07 (td, J=13.5, 6.8 Hz, 1H), 2.50 (s, 1H), 2.20(td, J=11.5, 10.0, 4.7 Hz, 2H), 2.14-2.09 (m, 1H), 2.01 (s, OH), 1.76(ddd, J=14.3, 10.7, 5.4 Hz, 2H), 1.69 (d, J=13.1 Hz, 1H), 1.38 (s, 3H),1.25 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 190.79, 171.32, 170.48, 170.32,163.90, 145.27, 143.69, 143.57, 139.37, 136.85, 131.43, 130.30, 130.20,125.37, 125.31, 124.05, 108.43, 72.00, 63.42, 56.43, 52.53, 51.31,45.65, 44.26, 43.76, 38.42, 35.85, 17.93, 16.82, 14.84. HRMS calculatedfor C₃₀H₂₉O₉N [M+NH₄]⁺: 565.2198 (found); 565.2186 (calcd). Meltingpoint: 229-232° C.

In Vitro Pharmacology

Cell culture and opioid receptor agonist activity assays proceeded asdescribed in Riley, A. P., Groer, C. E., Young, D., Ewald, A. W.,Kivell, B. M., and Prisinzano, T. E. (2014) Synthesis and kappa-opioidreceptor activity of furan-substituted salvinorin A analogues, J. Med.Chem. 57, 10464-10475 (incorporated herein by reference in its entiretyfor any and all purposes).

β-Arrestin-2 EFC Recruitment Assay.

The effect on β-arrestin-2 recruitment was evaluated using methods asdescribed in Crowley, R. S.; Riley, A. P.; Sherwood, A. M.; Groer, C.E.; Shivaperumal, N.; Biscaia, M.; Paton, K.; Schneider, S.; Provasi,D.; Kivell, B. M.; Filizola, M.; Prisinzano, T. E. (2016) Syntheticstudies of neoclerodane diterpenes from Salvia divinorum: identificationof a potent and centrally acting μ opioid analgesic with reduced abuseliability. J. Med. Chem. 59, 11027-11038 (incorporated herein byreference in its entirety for any and all purposes). Briefly, on day 1,˜80% confluent CHO-K1 OPRM1 β-arrestin-2 cells were detached fromculture plates using nonenzymatic cell dissociation buffer (LifeTechnologies, Thermo Fisher Scientific, Waltham, Mass.) and countedusing a hemocytometer. Cells were plated at 5000 cells/well in 20 μL ofCell Plating Reagent 2 (DiscoveRx, Fremont, Calif.) in 384-well tissueculture plates and incubated at 37° C. overnight. On day 2, stocksolutions of test compounds were generated in 100% DMSO to 5 mM. Thestock solutions were used to make 11 serial dilutions and then dilutedto yield 5× compound concentrations in assay buffer (Hank's BalancedSalt Solution [HBSS, Life Technologies] with 10 mM HEPES [LifeTechnologies]). The cells were treated with 5 μL of the test compoundsolutions, final concentration of 1× compound, and 1% DMSO. Cells wereincubated for 90 min at 37° C. Cells were then treated with detectionreagents, 12.5 μL per well, according to manufacturer's instructions andincubated at room temperature for at least 1 h protected from light.Luminescence was quantified using a Synergy 2 plate reader with Gen5Software (BioTek, Winooski, Vt.). Data were normalized to vehicle (nocompound, 1% DMSO final concentration) to remove any backgroundluminescence. The highest dose(s) of DAMGO was used as 100% recruitment,and all data was converted to percentages based upon the DAMGO response.Bias factors were calculated according to Equation 1, provided below:

$\begin{matrix}{{\log \mspace{14mu} \left( {{Bias}\mspace{14mu} {Factor}} \right)} = {\left( {\log \ \left( \frac{E\; {\max_{test}{\times {EC}\; 50_{DAMGO}}}}{{EC}\; 50_{test} \times E\; \max_{DAMGO}} \right)} \right)_{\beta - {arrestin}} - \left( {\log \mspace{14mu} \left( \frac{E\; {\max_{test}{\times {EC}\; 50_{DAMGO}}}}{{EC}\; 50_{test} \times E\; \max_{DAMGO}} \right)} \right)_{cAMP}}} & {{Eq}.\mspace{11mu} 1}\end{matrix}$

In Vivo Methods Details

Animal Studies.

Adult male B6-SJL mice (22-29 g) and male Sprague Dawley rats (240-350g) were housed on a 12 h light cycle and experiments were conductedduring the light cycle. All animals were bred and housed at the VictoriaUniversity of Wellington (VUW) small animal facility, New Zealand. Allexperimental procedures were approved by the VUW Animal Ethics Committeeand carried out in accordance to their guidelines for animal care. Foodand water were provided ad libitum except during experimentalprocedures.

Hot Water Tail-Flick Dose-Dependent Antinociceptive Effects:

To determine dose-dependent anti-nociceptive effects, the cumulativedose response will be carried out in mice following repeatedsubcutaneous (s.c.) injections in the as described in Bohn, L. M.,Lefkowitz, R. J., Gainetdinov, R. R., Peppel, K., Caron, M. G., and Lin,F. T. (1999) “Enhanced morphine analgesia in mice lacking beta-arrestin2”, Science 286, 2495-2498 (incorporated herein by reference in itsentirety for any and all purposes). Withdrawal latencies will bemeasured 30 min following each dose. ED₅₀ values will be calculated bynon-linear regression analysis from each individual curve using GraphPadPrism.

Hot Water Tail-Flick Tolerance Evaluation:

To measure the effect of tolerance, compounds were administered to micedaily for 9 days as described in Bohn, L. M., Gainetdinov, R. R., Lin,F.-T., Lefkowitz, R. J., and Caron, M. G. (2000) “[mu]-Opioid receptordesensitization by [beta]-arrestin-2 determines morphine tolerance butnot dependence,” Nature 408, 720-723 (incorporated herein by referencein its entirety for any and all purposes). Tail flick latencies weremeasured 30 min following administration on days 1, 3, 5, 7 and 9. Micegiven daily vehicle treatments were challenged with either morphine orcompound 3.46 on day 9 to show the prolonged exposure to the hot watertail immersion did not change the analgesic effects when compared to day1.

Accelerating Rotarod Performance Assay.

Motor incoordination will be assessed in mice using an acceleratingrotarod protocol using previously described methods, such as Deacon, R.M. (2013) “Measuring motor coordination in mice,” Journal of visualizedexperiments: JoVE, e2609 (incorporated herein by reference in itsentirety for any and all purposes). Mice will be initially trained onthe rotarod apparatus (Harvard Apparatus, MA, USA, 32 mm diameter) in 16sessions over a 4 day period. An accelerating procedure (4-40 rpm) witha 300 s cut-off will be used. Latencies will be measured as the timetaken for the animal to fall off the apparatus. On the test day, initialbaseline latencies for each animal will be measured in triplicate.Animals which are unable to consistently stay on the apparatus for atleast 240 s will be excluded from the experiment. Followingadministration of a compound of the present technology, morphine (10mg/kg, i.p.), or vehicle the latency to fall from the apparatus will bemeasured at 15, 30, 45, 60, 90, 120, 180 and 240 min. The percentagebaseline will be calculated at each time point by the equation: %baseline=(test latency/baseline latency)×100.

Conditioned Place Preference Assay.

The conditioned place preference will be evaluated using methods asdescribed in Piepponen, T. P., Kivastik, T., Katajamaki, J., Zharkovsky,A., and Ahtee, L. (1997) Involvement of opioid mu 1 receptors inmorphine-induced conditioned place preference in rats, Pharmacol.Biochem. Behav. 58, 275-279 (incorporated herein by reference in itsentirety for any and all purposes). Briefly, on habituation day (day 1)adult male Sprague Dawley rats (240-350 g) will be allowed to freelyexplore the 3-chambered place preference apparatus (PanLab HarvardApparatus) for 15 min to determine baseline preference using Smart 3.0software (PanLab). Animals exhibiting preference in the outercompartments (30×30×34 cm) of over 80% or over 40% in the centralcorridor (8×10×34 cm) will be considered exclusions. Conditioning willbe carried out on days 2-7 for 60 min with drug treatment (5 or 10mg/kg, i.p.) paired to the least preferred outer compartment and vehicle(DMSO:Polyethylene glycol at a ratio of 1:3 i.p) administered to thepreferred chamber in a counterbalanced design. On test day (day 8)conditioned preference will be determined in a single 15 min trial withfree access to the entire apparatus. Results will be reported as thedifference in the times spent on the drug-paired side versus thevehicle-paired side and One-way ANOVA with Bonferroni's multiplecomparisons tests used to determine statistical significance.

Representative Results

An in vitro comparison of representative compounds of the presenttechnology to kurkinorin was performed using a commercially availablefunctional assay that measures forskolin-induced cAMP accumulation inCHO cells stably expressing MOR, where the results are provided in Table1.

TABLE 1 MOR Potencies of Compounds of Present Technology vs. Kurkinorin.

Entry G² = EC₅₀ (nM)^(a,b) kurkinorin

1.2 ± 0.2 1

1.5 ± 0.6 2

9 ± 2 3

0.03 ± 0.01 4

2.42 ± 0.07 5

13 ± 3  6

0.19 ± 0.03 7

>10,000^(c) 8

2.2 ± 0.2 9

3.2 ± 0.7 ^(a)EC₅₀ = Effective concentration to produce 50% of themaximal response as measured by inhibition of cAMP accumulation in CHOcells expressing MOR. ^(b)E_(max) = 100%, unless otherwise noted.^(c)E_(max) = 0%.These results show that representative compounds of the presenttechnology are potent MOR agonists, where the compound of entry 6(compound 3.49) is almost an order of magnitude more potent thankurkinorin, and the compound of entry 3 (compound 3.46) is about twoorders of magnitude more potent than kurkinorin. Notably, testing showedthat each of the compounds of the present technology from Table 1exhibit EC₅₀ values for KOR>10,000 nM—thus, the compounds of the presenttechnology are highly selective for agonizing MOR over KOR.

Antinociceptive effects in the hot water tail-flick assay in mice wereexamined, where the results following daily administration of dosages ofthe compounds that provided max effect (10 mg/kg/i.p. morphine or 5mg/kg/i.p. compound 3.46) are provided in FIGS. 1A & 1B (n=4). Datashown in FIGS. 1A-B are mean±SEM. As illustrated by FIG. 1A, morphineshowed significant antinociceptive effects (expressed in % maximalpossible effect) on days 1 and 3 but not day 9. FIG. 1B furtherillustrates the change in antinoceptive effect of morphine on day 9compared to day 1. However, compound 3.46 surprisingly maintainedantinociceptive efficacy from days 1-9 (FIGS. 1A-AB). Daily vehicletreated mice display no antinociceptive effects days 1-9 (see FIG. 1A).

FIGS. 2A-B compare the results of a hot water tail-flick assay in micethat received a single i.p. injection of (a) 10 mg/kg morphine, (b) 5mg/kg compound 3.46, (c) 5 mg/kg compound 3.46 followingpre-administration of beta-funaltrexamine (“β-FNA”; 5 mg/kg, s.c), and(d) vehicle. FIG. 2A provides the time course of analgesic effects inthe hot water tail-flick assay and FIG. 2B provides an area under thecurve (“AUC”) analysis, where **p<0.01, ***p<0.001, ****p<0.0001, drugcompared to vehicle, #p<0.05, ##p<0.01, ###p<0.001, ####p<0.0001compared to morphine, {circumflex over ( )}{circumflex over( )}{circumflex over ( )}{circumflex over ( )}p<0.0001 3.46 compared to3.46+β-FNA. Data shown as mean±SEM (N=5-7 per group).

It is expected that compounds of the present technology (e.g., compound3.46) will exhibit less or essentially no decrease in motor coordinationas compared to morphine. For example, preliminary data in theaccelerating rotarod performance assay shows administration of compound3.46 exhibits significantly less effects on motor coordination thanmorphine. It is expected that compounds of the present technology (e.g.,compound 3.46) will exhibit essentially the same effects as vehicle inthe conditioned place preference assay as contrasted with morphine. Itis expected that compounds of the present technology (e.g., compound3.46) will show a significant decrease in preference compared tomorphine and rewarding effects will not be significantly different formvehicle.

An in vitro comparison of representative compounds of the presenttechnology to DAMGO, morphine, and fentanyl was performed using acommercially available functional assay that measures β-arrestin-2recruitment in CHO-K1 OPRM1 cells stably expressing a fusion protein ofβ-arrestin-2 and a mutant β-galactosidase, where the results areprovided in Table 2.

TABLE 2 MOR Potencies of Compounds of Present Technology vs. DAMGO.

EC₅₀ ± SEM^(a) (nM) (% Entry G² = Efficacy)^(b) Bias Factor DAMGO NotApplicable 42 ± 5 (97) 1.0 morphine Not Applicable 380 ± 40 (38) 0.36fentanyl Not Applicable 38 ± 2 (70) 0.34 kurkinorin

140 ± 40 (96) 0.57 1

 40 ± 10 (90) 2.62 2

490 ± 80 (84) 1.21 3

14 ± 1 (81) 0.14 4

150 ± 30 (75) 0.87 5

360 ± 80 (74) 1.98 6

 10 ± 3 (119) 1.57 7

>25000 (0) — 8

190 ± 60 (76) 0.65 9

260 ± 60 (88) 0.81 ^(a)Mean ± standard error of the mean; n ≥ 3individual experiments run in triplicate. ^(b)Maximum efficacy valuescalculated based on DAMGO maximum stimulation. ^(c)Bias factors werecalculated using Eq. 1. Values <1 indicate bias towards the cAMP pathwayand values >1 indicate bias towards the β-arrestin-2 pathway. DAMGO isthe reference compound, with a bias = 1.

While certain embodiments have been illustrated and described, a personwith ordinary skill in the art, after reading the foregoingspecification, can effect changes, substitutions of equivalents andother types of alterations to the compounds of the present technology orsalts, pharmaceutical compositions, derivatives, prodrugs, metabolites,tautomers or racemic mixtures thereof as set forth herein. Each aspectand embodiment described above can also have included or incorporatedtherewith such variations or aspects as disclosed in regard to any orall of the other aspects and embodiments.

The present technology is also not to be limited in terms of theparticular aspects described herein, which are intended as singleillustrations of individual aspects of the present technology. Manymodifications and variations of this present technology can be madewithout departing from its spirit and scope, as will be apparent tothose skilled in the art. Functionally equivalent methods within thescope of the present technology, in addition to those enumerated herein,will be apparent to those skilled in the art from the foregoingdescriptions. Such modifications and variations are intended to fallwithin the scope of the appended claims. It is to be understood thatthis present technology is not limited to particular methods, reagents,compounds, compositions, labeled compounds or biological systems, whichcan, of course, vary. It is also to be understood that the terminologyused herein is for the purpose of describing particular aspects only,and is not intended to be limiting. Thus, it is intended that thespecification be considered as exemplary only with the breadth, scopeand spirit of the present technology indicated only by the appendedclaims, definitions therein and any equivalents thereof.

The embodiments, illustratively described herein may suitably bepracticed in the absence of any element or elements, limitation orlimitations, not specifically disclosed herein. Thus, for example, theterms “comprising,” “including,” “containing,” etc. shall be readexpansively and without limitation. Additionally, the terms andexpressions employed herein have been used as terms of description andnot of limitation, and there is no intention in the use of such termsand expressions of excluding any equivalents of the features shown anddescribed or portions thereof, but it is recognized that variousmodifications are possible within the scope of the claimed technology.Additionally, the phrase “consisting essentially of” will be understoodto include those elements specifically recited and those additionalelements that do not materially affect the basic and novelcharacteristics of the claimed technology. The phrase “consisting of”excludes any element not specified.

In addition, where features or aspects of the disclosure are describedin terms of Markush groups, those skilled in the art will recognize thatthe disclosure is also thereby described in terms of any individualmember or subgroup of members of the Markush group. Each of the narrowerspecies and subgeneric groupings falling within the generic disclosurealso form part of the invention. This includes the generic descriptionof the invention with a proviso or negative limitation removing anysubject matter from the genus, regardless of whether or not the excisedmaterial is specifically recited herein.

As will be understood by one skilled in the art, for any and allpurposes, particularly in terms of providing a written description, allranges disclosed herein also encompass any and all possible subrangesand combinations of subranges thereof. Any listed range can be easilyrecognized as sufficiently describing and enabling the same range beingbroken down into at least equal halves, thirds, quarters, fifths,tenths, etc. As a non-limiting example, each range discussed herein canbe readily broken down into a lower third, middle third and upper third,etc. As will also be understood by one skilled in the art all languagesuch as “up to,” “at least,” “greater than,” “less than,” and the like,include the number recited and refer to ranges which can be subsequentlybroken down into subranges as discussed above. Finally, as will beunderstood by one skilled in the art, a range includes each individualmember.

All publications, patent applications, issued patents, and otherdocuments (for example, journals, articles and/or textbooks) referred toin this specification are herein incorporated by reference as if eachindividual publication, patent application, issued patent, or otherdocument was specifically and individually indicated to be incorporatedby reference in its entirety. Definitions that are contained in textincorporated by reference are excluded to the extent that theycontradict definitions in this disclosure.

The present technology may include, but is not limited to, the featuresand combinations of features recited in the following letteredparagraphs, it being understood that the following paragraphs should notbe interpreted as limiting the scope of the claims as appended hereto ormandating that all such features must necessarily be included in suchclaims:

-   A. A compound of Formula I:

or a pharmaceutically acceptable salt and/or solvate thereof, wherein

-   -   R¹ is

-   -   R² is a substituted C₁-C₃ alkyl, —C(O)H, —C(O)—C₁-C₃ alkyl, or        —C(O)—NR⁴R⁵, and        -   R³ is H, halo, substituted C₁-C₃ alkyl, or C₁-C₃ alkoxy; or    -   R² and R³ combined are heterocyclyl or heteroaryl; and    -   R⁴ and R⁵ are each independently H or C₁-C₃ alkyl.

-   B. The compound of Paragraph A, wherein    -   R² is a hydroxyl-substituted C₁-C₃ alkyl, a C₁-C₃ alkoxy        substituted C₁-C₃ alkyl, —C(O)—C₁-C₃ alkyl, or —C(O)—NR⁴R⁵.

-   C. The compound of Paragraph A or Paragraph B, wherein    -   R² is hydroxymethyl, (R)-1-hydroxyethyl, (S)-1-hydroxyethyl,        methoxymethyl, or —C(O)—NH₂.

-   D. The compound of any one of Paragraphs A-C, wherein R³ is H or R²    and R³ combined are heterocyclyl or heteroaryl.

-   E. The compound of any one of Paragraphs A-D, wherein when R² and R³    are combined, R¹ is

-   -   wherein X¹ and X² are each independently CH₂, O, or NH.

-   F. The compound of any one of Paragraphs A-E, wherein the compound    is

or a pharmaceutically acceptable salt and/or solvate thereof.

-   G. A composition comprising the compound of any one of Paragraphs    A-F and a pharmaceutically acceptable carrier.-   H. A pharmaceutical composition comprising an effective amount of    the compound of any one of Paragraphs A-F for treating pain in a    subject, and a pharmaceutically acceptable carrier.-   I. The pharmaceutical composition of Paragraph H, wherein the    subject is suffering from acute and/or chronic pain.-   J. A method comprising administering an effective amount of a    compound of any one of Paragraphs A-F to a subject.-   K. The method of Paragraph J, wherein the subject is suffering from    acute and/or chronic pain.-   L. A method comprising administering a pharmaceutical composition of    Paragraph H or Paragraph I to a subject in need thereof.-   M. The method of Paragraph L, wherein the subject is suffering from    acute and/or chronic pain.-   N. A method of binding the mu opioid receptor, the method comprising    contacting a mu opioid receptor with a compound of any one of    Paragraphs A-F.-   O. The method of Paragraph N, wherein the contacting comprises a    cell not within a patient.

Other embodiments are set forth in the following claims, along with thefull scope of equivalents to which such claims are entitled.

1. A compound of Formula I:

or a pharmaceutically acceptable salt and/or solvate thereof, wherein R¹is

R² is a substituted C₁-C₃ alkyl, —C(O)H, —C(O)—C₁-C₃ alkyl, or—C(O)—NR⁴R⁵, and R³ is H, halo, substituted C₁-C₃ alkyl, or C₁-C₃alkoxy; or R² and R³ combined are heterocyclyl or heteroaryl; and R⁴ andR⁵ are each independently H or C₁-C₃ alkyl.
 2. The compound of claim 1,wherein R² is a hydroxyl-substituted C₁-C₃ alkyl, a C₁-C₃ alkoxysubstituted C₁-C₃ alkyl, —C(O)—C₁-C₃ alkyl, or —C(O)—NR⁴R⁵.
 3. Thecompound of claim 1, wherein R² is hydroxymethyl, (R)-1-hydroxyethyl,(S)-1-hydroxyethyl, methoxymethyl, or —C(O)—NH₂.
 4. The compound ofclaim 1, wherein R³ is H or R² and R³ combined are heterocyclyl orheteroaryl.
 5. The compound of claim 1, wherein when R² and R³ arecombined, R¹ is

wherein X¹ and X² are each independently CH₂, O, or NH.
 6. The compoundof claim 1, wherein the compound is

or a pharmaceutically acceptable salt and/or solvate thereof.
 7. Acomposition comprising a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 8. A pharmaceutical composition comprising aneffective amount of a compound of claim 1 for treating pain in asubject, and a pharmaceutically acceptable carrier.
 9. Thepharmaceutical composition of claim 8, wherein the subject is sufferingfrom one or both of acute pain and chronic pain.
 10. A method comprisingadministering an effective amount of a compound of claim 1 for treatingpain to a subject in need thereof.
 11. The method of claim 10, whereinthe subject is suffering from acute pain.
 12. The method of claim 10,wherein the subject is suffering from chronic pain.
 13. A method ofbinding the mu opioid receptor, the method comprising contacting a muopioid receptor with a compound of claim
 1. 14. The method of claim 13,wherein the contacting comprises a cell not within a patient.
 15. Themethod of claim 10, wherein R² is a hydroxyl-substituted C₁-C₃ alkyl, aC₁-C₃ alkoxy substituted C₁-C₃ alkyl, —C(O)—C₁-C₃ alkyl, or —C(O)—NR⁴R⁵.16. The method of claim 10, wherein R² is hydroxymethyl,(R)-1-hydroxyethyl, (S)-1-hydroxyethyl, methoxymethyl, or —C(O)—NH₂. 17.The method of claim 10, wherein R³ is H or R² and R³ combined areheterocyclyl or heteroaryl.
 18. The method of claim 10, wherein when R²and R³ are combined, R¹ is

wherein X¹ and X² are each independently CH₂, O, or NH.
 19. The methodof claim 10, wherein the compound is

or a pharmaceutically acceptable salt and/or solvate thereof.